Evaluation of the relationship between serum dynamic thiol/disulfide levels and pulse wave velocity in patients diagnosed with hypoxic-ischemic encephalopathy

Introduction: Hypoxic ischemic encephalopathy (HIE) is a condition characterized by high morbidity and mortality resulting from perinatal asphyxia. In moderate-to-severe HIE cases, therapeutic hypothermia increases survival and improves neurological prognosis. HIE can affect the cardiovascular and renal systems due to its multisystemic involvement in addition to neurological effects. In this study, arterial stiffness and oxidative stress levels were evaluated in children diagnosed with HIE who underwent therapeutic hypothermia to investigate whether these markers could be used to predict long-term cardiovascular risk. Materials and Methods: In this prospective study conducted between May 2024 and May 2025 with the approval of the ADÜ Ethics Committee and BAP support, children diagnosed with HIE stages 2-3 who underwent therapeutic hypothermia in the ADÜ neonatal intensive care unit (n=44) were compared with healthy children of the same age and gender (n=44). The sample size was determined based on the results of a power analysis. Participants' birth histories, anthropometric measurements, neurological examinations (using the GMFCS scale), language development, and family histories were recorded in case report forms. Additionally, data on children diagnosed with HIE were obtained from the system. Arterial stiffness measurements were taken using the Mobil-O-Graph pulse wave device with the oscillometric method, and the average of three measurements was taken. Blood samples were collected from participants between 8:00 and 10:00 a.m. after a 12–14 hour overnight fast to measure serum total and native thiol levels. Informed consent was obtained from the families of all HIE and control group children included in the study. The necessary statistical analyses were performed for the research data, and the results were considered statistically significant when p < 0.05. Results: The age range of the participants was 3-10.5 (mean 6.6 ± ) years, and 53.4% were male. A significantly higher cesarean section rate was observed in the control group (p=0.003). Although birth weight measurements were similar, the birth weight percentile-SDS value was significantly lower in the HIE group (p=0.003). According to the modified Sarnat staging system, 86.4% of the patients were stage 2 HIE patients. 75% had a history of resuscitation, 75% underwent PBV, 54.5% underwent intubation and invasive mechanical ventilation support, and 27.3% received inotropic support. The average neonatal intensive care unit stay was 15.5 days, and 40.9% of the infants had seizures. Anthropometric measurements of weight, BMI and their corresponding percentile-SDS values were significantly lower in the HIE group (p<0.05). In the neurological examination classification according to GMFCS, advanced gross motor function impairment was detected in the HIE group (p=0.003). In terms of language development, 25% of children in the HIE group had delayed speech and 18.2% had speech impairment, while all of the control group were normal. (p<0.001). In the assessment of arterial stiffness, peripheral SBP, pulse pressure, NDH (PWV), and reflection magnitude were significantly higher than in the control group (p=0.023, p=0.011, p<0.001, p=0.014). Serum thiol/disulfide homeostasis showed a shift toward disulfide in the HIE group, but this difference was not statistically significant. Conclusion: Low birth weight, height percentile, and SDS in the HIE group indicate that growth retardation beginning in the perinatal period continues into the long term. The high need for resuscitation and ventilation in moderate to severe HIE cases, as well as low APGAR scores and high Thompson scores, reflect the clinical severity of asphyxia. In the average 6.5-year follow-up, low weight, height, and BMI SDS values suggest that this group is at risk for growth retardation in the long term. NDH (PWV), an indicator of arterial stiffness, was found to be significantly higher in the HIE group, indicating long-term vascular damage. The increased NDH and reflection magnitude in the HIE group, when evaluated together with language development delay, suggests that arterial stiffness may also affect the neurodevelopmental process. In the HIE group, while NDH, SBP, and reflection magnitude increased, there was no difference in the augmentation index, suggesting that early vascular changes begin particularly in the structural characteristics of large arteries. Although thiol/disulfide homeostasis shifted toward the disulfide side in the HIE group, it was not statistically significant, suggesting that thiol/disulfide parameters may be more effective in the acute phase, while the effect may be limited and compensable over time in subacute hypoxic conditions. In assessing oxidative stress, thiol/disulfide homeostasis should not be considered in isolation but in conjunction with other biomarkers. Long-term monitoring of individuals diagnosed with HIE is important not only from a neurological perspective but also for the vascular system, as it facilitates the development of early intervention opportunities. In this regard, multicenter and large-scale studies are required. Keywords: Neonatal Hypoxic Encephalopathy, Hypertension, Thiol/disulfide Homeostasis, Arterial Stiffness, Pulse Wave Velocity (PWV)